Ambry Genetics, a subsidiary of Tempus AI, has introduced GenomeNext, a clinical whole-genome sequencing test that aims to close diagnostic gaps left by conventional methods. The test uses a human pangenome for alignment and includes optional RNA analysis through GenomeReveal. It also incorporates ongoing reinterpretation through the Patient for Life program. The approach targets rare disease diagnosis, particularly in children with neurological or multisystem conditions. Kelly Hagman, vice president of medical affairs at Ambry Genetics, said the goal is not just another me-too product, but the best possible option.
Expanding beyond the exome
Clinical exome sequencing, which targets protein-coding regions, helped establish a new standard for rare disease diagnosis when Ambry introduced it in 2011. It can miss noncoding variants and structural alterations, however. Recent discoveries have highlighted the importance of noncoding regions, such as pathogenic variants in the small nuclear RNA genes RNU2-2 and RNU4-2, which are often missed by conventional exome testing. GenomeNext analyzes approximately 20,000 coding genes and noncoding regions, detecting structural variants, selected short tandem repeats, mitochondrial variants, and changes affecting SMN1 and SMN2.
The technology’s broader coverage increases diagnostic opportunities but demands more sophisticated interpretation. For a patient with a suspected genetic disorder, a negative sequencing result does not necessarily mean the answer isn’t in their DNA. The disease-causing variant may have been mapped incorrectly, dismissed as benign, or left unclassified. Even whole-genome sequencing can miss a diagnosis if the reference genome does not contain the patient’s genetic makeup.
GenomeNext builds on Ambry’s experience combining DNA and RNA analysis, first introduced in hereditary cancer testing. Its GenomeReveal offering provides optional RNA analysis to clarify the functional consequences of genetic variants, particularly those affecting RNA splicing. Intronic variants can disrupt normal transcript processing, and RNA analysis can provide evidence supporting their pathogenicity. About a third of RNA-eligible variants are in noncoding regions that only genome sequencing can pick up, making RNA testing particularly useful in the genome setting.
A recent Ambry case study illustrates how this approach can resolve longstanding diagnostic uncertainty. A 14-year-old girl with autism, developmental regression, seizures, cerebral volume loss, hearing loss, and swallowing difficulties had previously received negative trio exome sequencing results. Subsequent whole-genome sequencing identified two variants in the HGSNAT gene: a truncating variant and a deep intronic variant located on opposite copies of the gene. RNA analysis confirmed their pathogenicity, establishing a diagnosis of mucopolysaccharidosis type IIIC, or Sanfilippo syndrome type C.
This case highlights a limitation of conventional exome sequencing in recessive disorders, where a second disease-causing variant may remain undetected in noncoding DNA. Combining WGS with RNA analysis can uncover these variants and establish their functional impact, transforming inconclusive findings into clinically actionable diagnoses. The diagnosis provided answers for the family and enabled the patient’s enrollment in a clinical trial investigating emerging therapies. Ambry estimates that RNA analysis increases diagnostic yield by approximately 2–3 percentage points, based on published research and its experience with ExomeReveal.
Building on long-read sequencing
Despite these analytical advances, GenomeNext uses short-read WGS. Those reads are aligned to a reference, variants are identified, and computational methods prioritize findings for clinical interpretation. Short-read sequencing is established and increasingly affordable, but repetitive sequences, large structural variants, and complex rearrangements can remain difficult to resolve. Long-read sequencing addresses some of these limitations by capturing longer stretches of contiguous DNA.
Ambry is investigating long-read approaches through its Advanced Translational Genomics Laboratory and collaborations associated with the Genomics Research to Elucidate the Genetics of Rare Diseases consortium. Eligible patients with unresolved exome or genome results may undergo long-read sequencing through these research collaborations. This work remains separate from the commercial GenomeNext offering.
Using the human pangenome
GenomeNext’s most distinctive innovation may be its use of the human pangenome for sequence alignment. Unlike the conventional GRCh38 reference, the pangenome incorporates sequences from diverse genetic ancestries. Hagman said the company is the first lab to launch using the pangenome as a reference sequence. Most labs align to GRCh38, the genome reference based largely on individuals of European ancestry. The pangenome is multiethnic and multiracial.
The approach adds about a chromosome’s worth of additional DNA that could not be mapped before. By incorporating previously underrepresented sequences, pangenome alignment could reduce reference bias and improve variant detection. Hagman said the additional detection rate will particularly benefit nonwhite populations, given the European background of the previous reference.
Proactive Reanalysis Through Patient for Life
Ambry launched the Patient for Life program to address the temporal gap in genomic testing. Scientific knowledge advances long after initial results are reported. New gene-disease associations emerge, yet clinicians often do not request reanalysis. After about five years, requests decline significantly. The program aims to close this gap through proactive review.
GenomeNext patients are automatically enrolled in Patient for Life. No additional physician order or patient cost is required. Approximately 15 to 20 PhD-level scientists continuously review emerging research. They reassess gene-disease relationships to find clinical relevance in previously inconclusive findings. This process allows Ambry to revisit cases when new discoveries make older results actionable.
